Covalent targeted radioligands potentiate radionuclide therapy

Area of Science:

• Oncology
• Radiochemistry
• Medicinal Chemistry

Background:

• Targeted radionuclide therapy offers localized cancer irradiation but faces challenges in sustainable tumor targeting and rapid healthy tissue clearance.
• A key limitation is the dissociation of radiopharmaceuticals from target proteins, leading to suboptimal therapeutic outcomes.
• Developing strategies for sustained binding of radiopharmaceuticals to tumor-specific proteins is crucial for advancing cancer treatment.

Purpose of the Study:

• To engineer radiopharmaceuticals with a novel ligation strategy to achieve sustained tumor targeting and enhanced therapeutic efficacy.
• To investigate the use of sulfur (VI) fluoride exchange (SuFEx) chemistry for covalent conjugation of radiopharmaceuticals to tumor-specific proteins.
• To evaluate the performance of SuFEx-engineered radiopharmaceuticals in terms of tumor uptake, retention, imaging, and therapeutic outcomes in preclinical and pilot clinical studies.

Main Methods:

• Installation of a SuFEx chemistry-based linker onto radiopharmaceuticals to enable binding-to-ligation transition upon target engagement.
• Conjugation of engineered radiopharmaceuticals to tyrosine residues of target proteins via the SuFEx 'click' reaction.
• Evaluation of covalent binding, dissociation kinetics, tumor uptake, healthy tissue clearance, imaging, and therapeutic efficacy in mouse models and a pilot patient study.

Main Results:

• SuFEx-engineered fibroblast activation protein inhibitor (FAPI) demonstrated over 80% covalent binding and minimal dissociation for six days.
• SuFEx-FAPI showed a 257% increase in tumor uptake and a 13-fold greater tumor retention compared to original FAPI in mice, with rapid clearance from healthy tissues.
• Pilot imaging studies identified more tumor lesions in cancer patients using the SuFEx strategy, and targeted radionuclide therapy with SuFEx-engineered FAPI and a prostate-specific membrane antigen (PSMA) radioligand led to significant tumor regression in mice.

Conclusions:

• The SuFEx ligation strategy effectively creates radiopharmaceuticals with sustained tumor targeting and enhanced retention, overcoming key limitations of current targeted radionuclide therapies.
• This approach significantly improves tumor imaging and therapeutic efficacy, as demonstrated with FAPI and PSMA targets.
• The adaptability of SuFEx chemistry suggests potential for application to a broad range of cancer targets, offering a versatile platform for developing next-generation radiopharmaceuticals.